1-lower alkyl-4-cyclohexyl-4-lower fatty acyloxy-piperidines and acid addition salts thereof



Patented Feb. 21, 1950 l-LOWER .ALKYLA-CYCLOHEXY L-A-LOWER FAT-TYACYLOXY-PIPERIDINES AND ACID ADDITIGN SALTS THEREOF "John Lee, nEssexFells, and Leo Berger, Nutley, N. J., 'assignors to Hoffmann-Il'a 'RocheInc., Nutley, N. :L, aconporation of New Jersey No Drawing.ApplicationJuly 8, 1946, Serial No. 682,133

-:81Claims. (01. 260-294) The present invention relates to theproduction of N-tertiaryl-cyclohexyl p'iperidines which can berepresented by the following formula:

and their salts. In the above formula, Rstands for an alkyl radical, as,for example, a straight chain .or branched chain alkyl radical, R.stands for hydrogen or a lower alkyl group as, .for .ex-

ample, methyl, ethyl and the like; and Xstands for hydrogen or an acylgroup as, .for example, A

acetyl, propionyl, butyr-yl, valeryl, succinoyl, benzoyl, piperonyl,cinnamoyl, tropoyl, furoyl, pamino-benzoyl and the like. The compounds:in the above formula. when X is H are highly useful as intermediatesfor the preparation of or- .ganic compounds, for example, compounds ofthe above formula where X is .acyl. The acyloxy compounds have analgesicand spasmolytic properties.

In Danish Patent No. 60,592, published February 15,, 1943, there isdescribed the manufacture of compounds of the structural formula:

001 or COR) I H2 CH2 piperidines by employing 'cyclohexyl :magnesiumhalides, that a secondary reaction occurs so that only'a vanishinglysmall or noyi'eld of the cycle- ;hexyl piperidine compound is-obtained.

According to the present invention, we have found that1-alkyl-4-cyclohexy1-4 piperidinols can be prepared-in excellentyield'by direct hydrogenation of the corresponding 1-alkyl-4-phenyl-4-piperidinol salts. The reaction can be represented by the following"scheme:

In theabove formula, A is an anionof an organic or inorganicacid-'stronger-thanacetic'acid, as, for example, Cl, N03, H804, citrate,tartrate, ethane-sulfonate andsimilar anions. Rand -R have the samesignificance as in the general' formula A.

'The hydrogenation of the-'4-phenyl-4 piperidinol salts ispreferably-carried out in solution and in the presence of a catalyst,for example, a platinum catalyst at a temperature above "C. but below atemperature at which char-ring would occurypre'ferablyin the rangeof-8'0-130PC. and at a superatmospheric pressure, "preferably 500 poundsor upward. While lower pressures may be employed, lower temperatures are'notas satisfactory. Other catalysts than platinum may be employed, as,for example, palladium. Any "suitable solvents for the4-p'henyl-4-piperidino1 salts canbe employed, as, for example, water,alcohols, such as methanol, ethanol, isopropanol; "dioxane, ethylacetate, and the like.

The fact that cycloh'exyl compounds are obtained according to ourprocessis unexpected in that in applying :the same reaction conditions directlyto the esters of .the l-ialkyl-e-aryllpiperidinols, none of the desired-1 alkyl-4cyclowhexyl-l-acyloxy compoundcan --be isolated. This isbelieved to be due to hydrogenolysis occurring which eliminates theacyloxy group entirely. On applying the same reaction, however, to theunacylated 1-alkyl-4-phenyl-4-piperidinol, the described compounds wereobtainedthe tertiary hydroxyl group being surprisingly resistant tohydrogenolysis.

As specific examples of compounds that can be prepared by theabove-described method are the following:

1methyl-4-cyclohexyl-4-hydroxy piperidine l-methyl-3-methyl-4hydroxy-4-cyclohexyl piperidine 1-isopropyl 4 hydroxy-4-cycloh'exylpiperidine 1-butyl-4-cyclohexyl-4-hydroxy piperidine, and

theirsalts.

The above piperidinols and others obtained by the present method can beacylated by means of acid anhydrides or acyl halides to obtain thecorresponding 1-alkyl-4-cyclohexyll-acyloxy piperidines. The acyl groupsmay be lower fatty-acyl residues, such as acetyl, propionyl, butyryl,valeryl, succinoyl, etc.; or may be lower aromatic acyl residues as, forexample, benzoyl, piperonyl, etc.; or aryl-aliphatic as, for example,cinnamoyl, tropoyl; or substituted aromatic acyl such as pamino-benzoyl;or heterocyclic acyl, as, for ex ample, furoyl. These groups areintroduced by acylating the 4-cyclohexyl piperidinols with thecorresponding anhydrides and acyl chlorides.

EXAMPLE 1 1-butyl-4-cyclohexyl-4-hydroxy-piperidine 8.0 grams ofl-butyl-l-phenyl-4-hydroxy piperidine hydrochloride is dissolved in 100cc. of alcohol and hydrogenated in the presence of Adams platinumcatalyst at 85 C. under pressure of 1100 lbs. of hydrogen for severalhours. When the hydrogen absorption ceases the catalyst is filtered offand the alcoholic solution con centrated to dryness. The residue onrecrystallization from acetone yields l-butyl-4-cyclohexyl- 4-hydroxypiperidine hydrochloride melting at 223.5- 225.5 C.

The hydrochloride on treatment with alkali yields the base which oncrystallization from normal hexane isobtained in the form of colorlessneedles melting at 96-98 C.

The crystalline base is converted to the 4-acyloxy compounds bytreatment with an acid anhydride, catalyzed with a drop of sulfuricacid, on the steam bath for four hours. The products obtained areconverted to the crystalline hydrochlorides and purified byrecrystallization from a mixture of ethyl acetate and methanol. In thismanner the 4-acetoxy, -propionoxy, and the 4- butyroxy derivatives ofl-butyll-hydroxyl-cyclohexyl piperidine are prepared, by employingacetic, propionic, and butyric acid anhydrides, respectively as theacylating agents.

(a) lbutyl-4=- cyclohexyl 4 acetoxy piperidine hydrochloride, M. P.229-230 (b) l-butyll-cycloh exyl 4 propionoxy P113811! dinehydrochloride, M. P.'224225 (c) 1-bllty1-4-CYClOhBXYl-l-blltYIOXYpiperidine hydrochloride, M. P. 202.5 (decomp.)

EXAIVIPLEZ I the presence of 1 gram of Adams platinum cata lyst. Aftercompletion of the absorption of hydrogen, the catalyst is filtered offand the solution concentrated to dryness. The crystalline residue onrecrystallization from acetone-methanol gives1-methyl-4-cyclohexyl-4-hydroxy piperidine hydrochloride, M. P. 203205C.

The hydrochloride is converted to the free base and treated in themanner described with propionic anhydride and a drop of cone. H2804, onthe steam bath for 4 hours. The product obtained is converted to thehydrochloride and purified by recrystallization from ethyl acetate andmethanol to yield colorless crystals melting at 212-214=. The product is1-methyl-4-cyc1ohexyl-4-propionoxy piperidine hydrochloride.

EXAMPLE 3 1-isopropyZ-4-cycZohexyZ-sl-hydroxy piperidine C CH3 6.6 gramsof 1-isopropyl-4-phenyl-4-hydroxy piperidine hydrochloride, obtained asdescribed in application Serial No. 682,131, filed July 8, 1946 aredissolved in cc. of alcohol and hydrogenated for 4 hours at C. under thepressure of 1000 lbs. of hydrogen in the presence of 600 mg. of platinumoxide catalyst. The reaction absorbs the theoretical amount of hydrogen.The solution is then filtered from the catalyst and concentrated todryness and the residue on recrystallization from acetone and methanolmixture yields colorless crystals having a M. P. 232-234" C. The productobtained is l-isopropyl- 4-cyclohexyl-4-hydroxy piperidinehydrochloride.

The above compound can be acylated by heating the piperidinol base withpropionic anhydride in pyridine solution for 3 hours under reflux. Theproduct obtained is purified by recrystallization from acetone-methanoland occurs as colorless crystals melting 220-221 C. This compound is1-isopropyl-4-cyclohexyl-4-propionoxy piperidine hydrochloride.

EXAMPLE 4 1,3-dimethyZ-4-cyclohexyl-4-hydromy piperidine 3 grams of1,3-dimethyl-4-phenyl-4-hydroxy piperidine are dissolved in 100 cc. ofalcohol and 1.5 cc. of concentrated hydrochloric acid is added. Thesolution is hydrogenated under 1000 pounds of pressure of hydrogen at 80C. for 3 hours in the presence of 600 mg. of Adams platinum catalyst.After cooling, the catalyst is removed by filtration and the filtrate isevaporated to dryness. The residual white salt, which cor responds tothe formula of 1,3-dimethyl-4-cyclohexyl--hydroxy piperidinehydrochloride, recrystallized from acetone-methanol, melts at 243-244"C. The salt as obtained above is dissolved in water, alkalinized withsodium hydroxide and the resultant base is extracted with ether. Theethereal solution after drying over sodium sulfate is distilled down andthe resultant free base dissolved in 10 cc. of propionic anhydride andone drop of concentrated sulfuric acid is added as a catalyst. Themixture is heated on a steam bath for 3 hours, the larger part of thepropionic anhydride removed in vacuum, and the residue poured onto anice bath. This is extracted with ether, the ethereal solution is driedover sodium sulfate for 12 hours, filtered and hydrogen chloride ispassed into the filtrate. A hydrochloride separates out, which onrecrystallization from ethyl acetate yields colorless, shiny crystalsmelting at 205-6 C. This compound corresponds to the formula for1,3-dimethyl-4- cyclohexyl-4-propionoxy piperidine hydrochloride.

Instead of employing the piperidinol hydrochloride salt as the startingmaterial in the above examples, one can employ other salts as, forexample, the N03, H304, citrate, tartrate and ethane sulfonate salts ofthe piperidinols. The salts are prepared by reacting the freepiperidinol bases with the corresponding acids in a manner similar tothat illustrated in the examples in connection with forming thehydrochloride salt.

We claim:

1. l-lower alkyl-4-cyclohexyl-4 -lower fatty acyloxy-plperidines andtheir acid addition salts.

REFERENCES CITED The following references are of record in the file ofthis. patent:

UNITED STATES PATENTS Number Name Date 2,151,047 Preisewerk et a1 Mar.21, 1939 FOREIGN PATENTS Number Country Date 60,592 Denmark Feb. 1, 1943309,300 Great Britain Apr. 11, 1929 409,732 Great Britain May 1, 1934OTHER REFERENCES Ser. No. 361,888, Scheuing et al. (A. P. C.) publishedApril 20, 1943.

1. 1-LOWER ALKYL-4-CYCLOHEXYL-4 - LOWER FATTY ACYLOXY-PIPERIDINES ANDTHEIR ACID ADDITION SALTS.